Pathways underlying recovery of injured urethral sphincter and a novel regenerative biomaterial intervention

项目总结 横纹外括约肌功能障碍是压力性尿失禁的最强预测因子， 定义为在没有膀胱的情况下，由于腹内压力增加而导致的非自愿性排尿 收缩。压力性尿失禁影响大约1/2的女性在她们生命中的某个时刻。这个 慢性压力性尿失禁发生背后的主要刺激事件是明确的 被确认为对女性在阴道分娩期间的尿失禁机制的损伤。这 令人震惊的普遍状况极大地降低了生活质量，导致显著的发病率，并 给个人和社会带来巨大的经济负担。尽管如此，预防性策略是 几乎不存在，可用的治疗是延迟和补偿的，因为它们不直接针对 潜在的病理生理学。这在很大程度上是因为我们对这些途径的理解 产后残留物导致尿道外括约肌固有肌肉成分衰竭 有限的。此外，目前流行的临床前研究并没有使用生物学上相关的怀孕动物模型。 出生损伤的证据。为了解决现有的未得到满足的临床需求和知识差距，我们收集了一个交叉- 具有不同但互补的专业知识的纪律团队，以执行当前项目 基础科学、生物材料开发和转化医学。我们将使用一种经过验证的生物 相关的妊娠临床前模型，可多次研究结构、分子和细胞事件 横跨产伤后横纹外括约肌的恢复连续体。这些基本 过程将为提供新的微创组织的发展和关键时间提供信息- 预防和治疗尿道肌功能障碍的工程疗法。具体来说，我们将测试一个 新型促再生骨骼肌特异性可注射细胞外基质水凝胶，源自 脱细胞猪骨骼肌预防和逆转外尿路适应不良恢复 产伤后的括约肌。总的来说，这项创新的研究将提供关于 参与调节外括约肌再生的生物过程，以及 低成本脱细胞微创支架作用的全面功能相关性评估 再生疗法，以对抗现有的尿失禁流行。

PROJECT SUMMARY Dysfunction of the striated external urethral sphincter is the strongest predictor of stress urinary incontinence, defined as involuntary loss of urine due to increased intraabdominal pressure in the absence of bladder contraction. Stress urinary incontinence affects approximately 1 in 2 women at some point in their lives. The primary inciting event behind the development of chronic stress urinary incontinence has been unequivocally identified as injury to the urinary continence mechanism sustained by women during vaginal deliveries. This astoundingly prevalent condition dramatically decreases quality of life, causes significant morbidity, and is associated with large economic burden to the individuals and society. Despite this, preventative strategies are almost non-existent, and the available treatments are delayed and compensatory as they do not directly target the underlying pathophysiology. The above is largely due to the fact that our understanding of the pathways that lead to failure of the intrinsic muscular components of the external urethral sphincter following birth injury remains limited. Furthermore, the prevailing preclinical studies do not utilize biologically relevant pregnant animal model of birth injury. To address the existing unmet clinical need and knowledge gaps, we assembled a cross- disciplinary team with diverse but complimentary expertise to execute the current project at the interface between basic science, biomaterial development, and translational medicine. We will use a validated and biologically relevant pregnant pre-clinical model to investigate structural, molecular, and cellular events at multiple time points across a recovery continuum of the striated external urethral sphincter following birth injury. These basic processes will inform the development of and the critical time to deliver new, minimally invasive tissue- engineered therapy for the prevention and treatment of urethral muscle dysfunction. Specifically, we will test a novel pro-regenerative skeletal muscle-specific injectable extracellular matrix hydrogel, derived from decellularized porcine skeletal muscles, in preventing and reversing maladaptive recovery of the external urethral sphincter following birth injury. Collectively, this innovative study will provide fundamental knowledge of the biological processes involved in the regulation of external urethral sphincter muscle regeneration, and comprehensive functionally relevant assessments of the role of low-cost acellular minimally invasive regenerative therapy to counteract the existing epidemic of urinary incontinence.